Insulin Autoimmune Syndrome (Hirata Disease)

Abstract

The insulin autoimmune syndrome (IAS), or Hirata’s disease, is characterized by the combination of fasting hypoglycemia, high concentration of total immunoreactive insulin, and presence of autoantibodies to native human insulin in serum. Since Hirata et al. first described the disease in 1970, there have been 330 reported cases of IAS during the past 37 years in Japan. IAS is the third leading cause of spontaneous hypoglycemia in Japan while only 47 cases in Caucasians and 20 cases in East Asians excluding Japanese have been reported in the past 37 years. Insulin autoantibodies production is classified as monoclonal or polyclonal, with the majority of IAS cases classified as polyclonal. A striking association between human leukocyte antigen (HLA) class II alleles DRB1*0406/DQA1*0301/DQB1*0302 and Japanese IAS cases with polyclonal insulin autoantibodies, which we found in 1992, has been well confirmed. Glutamate at position 74 in the HLA-DR4β1-chain was shown to be essential to the production of polyclonal insulin autoantibodies in IAS, whereas alanine at the same position of the HLA-DRβ1-chain might be important in the production of monoclonal insulin autoantibodies. Another interesting finding is an exposure of reducing compounds with SH group ahead of development of IAS. After reducing human insulin, T-cell recognized fragmented human insulin molecule in the context of DRB1*0406 molecules. Although methimazole was a representative reducing compound for the development of IAS before 2003, an increasing number of alfa lipoic acid-induced IAS has been recently remarkable.